IL-6 is a pleiotropic cytokine with a wide range of biological activities in the fields of immune regulation, hematopoiesis, inflammation and oncogenesis. It is produced by numerous cell types and acts on a large and diverse population of cells and tissues. Binding of IL-6 to the IL-6 receptor leads to the recruitment and complex formation of two gp130 molecules at the cell membrane. The intracellular dimerization of two gp130 proteins recruits members of the Janus family of tyrosine kinases (JAKs) to the complex, allowing trans-phosphorylation. JAKs subsequently phosphorylate additional targets, including the gp130 receptor, whose phosphorylation is necessary for the phosphorylation and activation of the signal transducers and activators of transcription (STAT), mainly STAT3 and STAT1. Activation of STATs leads to the formation of stable STAT complexes due to either homo- or heterodimerization. The phosphorylation and dimerization of the STAT-protein also exposes its nuclear localization signal, leading to translocation of the complex to the nucleus for binding to the promoter region of target genes, including cyclin D, c-myc, p21, p2′7, Bcl-2 and VEGF.
In a healthy organism, IL-6 is expressed at low levels controlled by a complex network comprising e.g. glucocorticoids and catecholamines. However, accumulating evidence indicates pathological roles for IL-6 in various disease conditions, including autoimmune, inflammatory and malignant diseases. These conditions are coupled to enhanced activation of the IL-6 signaling pathway, and the unchecked production from the IL-6 target genes may arise due to mutations in one or several different steps/proteins in the pathway. Normally the STAT3 activation is tightly regulated and activated STAT3 proteins are dephosphorylated by phosphatases and transported out of the nucleus. Aberrant and deregulated STAT3 promotes cell proliferation and cell survival in both solid and hematological tumors, including breast, lung, brain, colon, prostate, lymphoma and leukemia.
Also, the IL-6 signaling pathway is coupled to the Ras/MAPK- and PI3K signaling pathways. These are the major signaling patways regulating e.g. proliferation, survival and differentiation of cells, and they are frequently mutated in a variety of human diseases, including cancer and inflammatory diseases. For instance, aberrant regulation of the transcription factor NF-κB in the PI3K-pathway is associated with cancer development and progression, as well as in resistance to chemotherapy. Further, there is significant interactions (cross talk) between NF-κB and STAT3, including overlapping genes, co-transcription and co-localization, and thereby, NF-κB and STAT3 cooperate to promote development of several cancers.
(−)-Galiellalactone is a natural product isolated from wood-inhabiting fungi with submicromolar inhibition of IL-6/STAT3 signaling.
Nussbaum et al reports in Eur. J. Org. Chem. 2004, 2783-2790 on the modification of individual functional groups of (−)-galiellalactone. Most of the resulting analogues, however, turned out to be inactive or less active than (−)-galiellalactone.
Weidler et al reports in FEBS Letters 2000, 484, 1-6 that the biological effect of (−)-galiellalactone seemingly is due to a direct inhibition of the binding of STAT3-dimers to their regulatory elements.
U.S. Pat. No. 6,512,007 describe the use of galiella lactone as a pharmaceutical for the treatment of e.g. inflammatory processes.
The treatments for prevention, revocation or reduction of deceases like e.g. cancer are in many ways insufficient. Hence, compounds effective in modulating or inhibiting the above described IL-6/STAT signaling and/or PI3K/NF-κB signaling are desired.